Volume 182 Issue 4

Despite recent and largely undeserved adverse publicity, mefloquine remains a useful antimalarial Although malaria causes most suffering among children in the tropics, it should not be forgotten that it remains a major cause of military casualties. In September 2003, about 300 US Marines and support staff were deployed to Liberia, West Africa. Of those troops who spent at least one night ashore, 69 contracted falciparum malaria, an attack rate of 44%.1 Forty-four required evacuation for medical care to Europe or the United States. While none died, several developed cerebral malaria and required mechanical ventilation. Malaria was also common among Australian Defence Force (ADF) personnel deployed to East Timor between 1999 and 2000, with 385 cases reported, an attack rate of 5%.2 Eighty-four per cent of these cases were caused by Plasmodium vivax, which, while not life-threatening, causes significant morbidity. Relapse of P. vivax infection, caused by the re-emergence into the bloodstream of parasites lying dormant in the liver (so-called hypnozoites), was a major problem in this group, with 96 relapses reported despite 2 weeks of primaquine therapy.2 This pattern of infection is frequently observed in patients who contract malaria elsewhere in Asia and the Pacific, as reported by Charles and colleagues in this issue of the Journal.3 Nevertheless, effective chemoprophylaxis is readily available for Australian travellers. The challenge for medical practitioners is to select the most appropriate regimen and then to convince patients to use it. Malaria chemoprophylaxis for areas with chloroquine-resistant malaria* (including the Pacific Islands, South-East Asia, the Indian subcontinent, China, Africa and South America)4 Atovaquone + proguanil 250 mg + 100 mg (child > 40 kg and adult) 1 tablet orally, daily (starting 1 to 2 days before entering, and continuing until 7 days after leaving, malarious area) OR Doxycycline (child > 8 years: 2 mg/kg up to) 100 mg orally, daily (starting 2 days before entering, and continuing until 4 weeks after leaving, malarious area) OR Mefloquine (child 15 to 19 kg: tablet; 20 to 30 kg: tablet; 31 to 40 kg: tablet) 250 mg orally, weekly (starting 2 to 3 weeks before entering, and continuing until 4 weeks after leaving, malarious area). * Whatever chemoprophylaxis is prescribed, patients should be counselled that no prophylaxis is 100% effective, and the importance of mosquito avoidance should be emphasised. Mefloquine as chemoprophylaxisMuch has been written (and broadcast) about the neuropsychiatric side effects of mefloquine. While a number of class actions have been instituted, none has as yet reached resolution. Identifying malaria chemoprophylaxis with any confidence as the cause of major psychiatric illness or behavioural disturbance is problematic,5 even more so during or soon after exposure to an extremely stressful military environment. This issue is illustrated by allegations that mefloquine was responsible for fatal assaults committed by Canadian soldiers in Somalia and British soldiers in Sierra Leone, and that it contributed to the killings of spouses by US soldiers recently returned from Iraq. Similarly, it was alleged that psychiatric morbidity among ADF personnel who had been deployed to East Timor was attributable to mefloquine therapy. While it is reassuring that in this issue of the Journal, Kitchener and colleagues report no excess morbidity among ADF personnel taking mefloquine prophylaxis,6 the issue of tolerability of mefloquine is a real one. A double-blind, randomised controlled trial of malaria chemoprophylaxis comparing mefloquine and atovaquone–proguanil (Malarone [GlaxoSmithKline]) found that 139 of 483 (29%) participants taking mefloquine experienced an adverse neuro-psychiatric side effect, most commonly insomnia or strange or vivid dreams.7 Such side effects were reported in 69 of the 493 (14%) participants taking atovaquone–proguanil. The overall frequency of adverse events was similar in the two groups (71% and 67%, respectively), but the events were sufficiently severe to require discontinuation of the drug in 5% of those taking mefloquine versus 1.2% of those taking atovaquone–proguanil. Assessing tolerance to mefloquine before exposure (as undertaken by the ADF) might identify many of those intolerant of this drug, allowing an alternative agent to be selected. Alternative agents for chemoprophylaxisIn Australia, doxycycline is the most widely prescribed drug for malaria chemoprophylaxis. While its side effects are relatively benign (eg, thrush, photosensitivity and oesophagitis), the challenge is to ensure compliance. Numerous studies have demonstrated that adherence to a daily prophylactic regimen is unsatisfactory, especially among those requiring long-term protection.8 Atovaquone–proguanil is highly effective for chemoprophylaxis, but is costly and, like doxycycline, must be taken daily. There has been a resurgence of interest in primaquine as chemoprophylaxis, a drug generally used to prevent relapse of P. vivax. However, it too must be taken daily for prophylaxis and, like many other old “off-patent” orphan drugs, it is inordinately expensive. Tafenoquine, a much-anticipated drug related to primaquine, is now in phase III clinical trials. After three well-tolerated loading doses, a single monthly dose appears protective.9 However, like primaquine, it can cause severe haemolysis in patients with glucose-6-phosphate dehydrogenase deficiency. Thus, it is necessary to screen for this condition before beginning the drug. New agents for treating malariaAs Davis and colleagues discuss in this issue, artesunate is a highly effective and well tolerated antimalarial agent.10 It belongs to the artemesinin class of drugs derived from the Chinese wormwood plant qinghaosu, and is taken by many expatriates as “emergency standby treatment” at the first sign of fever (unpublished observation). While this practice is effective, particularly when combined with appropriate diagnostic tests, such as the rapid antigen test used in the case reported in this issue by Howden and colleagues,11 it is not without risk. The very short half-life of the active metabolite, dihydroartemesinin, means that any parasites remaining in the blood after a short course of therapy may not be cleared, leading to recurrent parasitaemia.10 Suitable drugs to combine with artesunate include mefloquine, doxycycline (if taken for one week), or, in the few regions where these drugs remain effective, combined pyrimethamine and sulfadoxine.10 Further risks of relying on emergency standby treatment alone include failing to recognise non-classical symptoms of malaria (such as diarrhoea), and exhausting drug supplies through premature self-medication for non-malarial illnesses. Of note, counterfeit artesunate is offered for sale in several Asian countries where pharmaceuticals are unregulated; the only artemisinin derivative available in Australia is artemether in combination with lumefantrine.10 A malaria vaccineAn effective malaria vaccine suitable for non-immune soldiers, travellers and the even larger population of residents of malaria-endemic countries remains a priority. The long-standing search for a vaccine has been invigorated by the creation of the Malaria Vaccine Initiative, a public–private partnership supported by the Bill and Melinda Gates Foundation. The recently published phase II malaria vaccine trial in Mozambique involving this initiative and GlaxoSmithKline Biologicals is an example of the productivity of this partnership.12 While the vaccine produced a statistically significant level of protection (29.9% to 57.7%), it is likely that, for now, doctors will continue to advise mosquito avoidance and to reach for the prescription pad rather than the vaccine refrigerator when preparing patients for trips to malarious areas.

James S McCarthy FRACP, MD

What is the evidence? Venous thrombosis and pulmonary embolism continue to be significant complications of hip or knee replacement surgery. Seven to 10 days of anticoagulant prophylaxis starting before or soon after surgery fail to prevent 20%–30% of venous thromboembolic events. It is this residual thrombosis rate that provides a spur for adding pre-discharge screening to routine prophylaxis, with the aim of detecting and treating silent thrombosis before it progresses to clinical disease. In this issue of the Journal, O’Reilly and colleagues (page 154) report on routine venous ultrasound examination performed on almost 6000 patients before discharge from hospital 6–7 days after major joint surgery. Within this large cohort, subclinical deep vein thrombosis (DVT) was detected in 9%, 26% and 37% of patients after hip, knee or bilateral knee replacement, respectively. This was despite intensive in-hospital prophylaxis using an anticoagulant (mostly low-molecular-weight heparin) plus intermittent calf compression and the use of elastic stockings. Thrombosis was proximal (affecting the popliteal, femoral or iliac veins) in 1.5%, 1.3% and 1.1% of patients after hip, knee or bilateral knee replacement, respectively. When considering how best to use this information, we should ask several questions. First, is ultrasonography reliable for detecting subclinical DVT? Although it is preferred for investigating clinically suspected disease, opinions are divided about its value in screening for subclinical thrombi, which are often no more than a few centimetres long. Ultrasonography is observer-dependent, and screening by this method has not been validated through large, blinded comparisons with the “gold standard” of bilateral venography. However, an excellent systematic overview of ultrasonography2 has reported a positive predictive value for subclinical proximal DVT of over 80% if disease prevalence is low and the false positive rate is no more than 5% (results with calf DVT were less impressive). So the 1%–1.5% proximal DVT rate reported by O’Reilly et al is probably valid. Second, are the DVT rates seen by O’Reilly et al consistent with previously reported results of routine venography? The answer is yes. Overall DVT rates 5–10 days after hip replacement in people given warfarin, low-molecular-weight heparin, fondaparinux (a specific inhibitor of activated factor X) or ximelagatran (an oral thrombin inhibitor) have been shown to be about 20%, 10%, 4%, and 8%, respectively, while proximal DVT rates are about 5%, 2%, 1.5%, and 3%, respectively.3, Reported rates of DVT after knee replacement are also consistent.3, If anything, the rate of proximal DVT found by O’Reilly et al is on the low side, perhaps because they combined chemical with physical prophylaxis and/or because ultrasound examination is less sensitive for detecting proximal DVT than is venography. Third, does ultrasonographic screening at discharge bring any clinical benefit? We just do not know. Logic suggests it should, but attempts to validate the value of pre-discharge screening by randomised trials have failed. Perhaps the trials were underpowered to detect real but small reductions in rates of venous thromboembolism. Or perhaps it is a wrong assumption that new thrombus formation is not a problem once patients leave hospital. We now know that thrombosis risk after major joint (especially hip) surgery persists for at least 4–6 weeks and that duration of prophylaxis is a major determinant of success. The rates of venous thromboembolism (subclinical, symptomatic and confirmed) in randomised comparisons are substantially reduced by persisting with preventive therapy until 4–5 weeks after a hip fracture or hip replacement rather than stopping (as in the study by O’Reilly et al) when patients are discharged from hospital.3,5,6 Hence, the recent recommendation by the American College of Chest Physicians (ACCP) for at least 10 days’ prophylaxis after major joint surgery, extending to 28–35 days after hip arthroplasty or hip fracture.3 The obvious explanation for reduced rates of venous thromboembolism is suppression of late thrombus formation. More intriguing is the apparent resolution of small venous thrombi formed soon after surgery — an effect best seen in one of the fondaparinux trials (the “PENTHIFRA-Plus” trial),5 in which the venographically detected thrombosis rate with ongoing prophylaxis was negligible (1.4%) 4 weeks after hip fracture surgery and well below the 8.3% rate previously found after 7 days of preventive therapy.6 (The latter rate is similar to the 9% DVT rate observed by O’Reilly et al after 1 week of intense prophylaxis.) By contrast, the thrombosis rate after 4 weeks among PENTHIFRA-Plus trial patients given a placebo following 1 week of fondaparinux therapy was 35%,5 a figure much higher than the 8.3% observed after 7 days in the earlier trial.6 The high DVT rates observed by O’Reilly et al confirm that in-hospital prophylaxis alone is not enough. Many would argue that extended prophylaxis is likely to be the simplest, cheapest and perhaps safest solution. Even if pre-discharge screening for subclinical disease might pre-empt the need for continued prophylaxis, there remain significant questions of resource availability, cost and possible harm. Ultrasound examination alone, if done in all patients and followed by further testing in the 9% or 26% of patients with thrombosis after unilateral hip or knee surgery, would cost (at current Medicare Benefits Schedule rates) about $200 000 per 1000 patients. The approach of O’Reilly et al was to treat all clots, regardless of their extent or position, with full doses of an anticoagulant for at least 2 weeks. This includes silent clots in the soleus or gastrocnemius muscle veins whose natural history is uncertain and perhaps mostly benign.7 But any decision to use anticoagulant therapy must balance potential benefit with likely bleeding risk. In this case, both remain unknowns, as the authors do not report on treatment complications. Evidence-based recommendations by expert groups are not prescriptions, and require judgement when applied to clinical practice. Even so, we should note the recent, firm (Grade 1A) recommendation by the 7th ACCP Conference on Antithrombotic and Thrombolytic Therapy3 against routine screening for DVT after major joint surgery, based on the lack of any demonstrable clinical effectiveness or cost-effectiveness of such screening.

Alexander S Gallus MB BS, FRCPA FRACP

The UK needs to revitalise metropolitan medicine as Australia has done for rural medicine With over half of the world’s population living in cities and towns, one of the great challenges of the 21st century is to define and deliver effective and affordable health and social care to urban populations. In the United Kingdom, this is nowhere more apparent than in the deprived parts of its great metropolitan areas. Here, the ratio of general practitioners to population numbers is significantly lower than the national average, there are more solo-doctor practices, and these practices frequently lack the critical mass required to support a full range of services. Overall, inner-city general practice has been a running sore for the National Health Service. To make matters worse, many of the principals of these practices are within cooee of retiring. . . country practitioners in Australia . . . are rediscovering the independence and ingenuity that the nation holds as central to its self-image The looming crisis in metropolitan medical manpower has thrown into focus a general difficulty in attracting health professionals of all kinds to work specifically in primary care, but also in other parts of the NHS serving the big cities. As ever, London is the most extreme case, but it is not unique. The combination of low wages, expensive accommodation, and difficulties in out-of-hours travel (underground trains stop soon after midnight and buses are then infrequent) leaves one far short of Dr Finlay’s idyllic country practice, as depicted in A J Cronin’s books and the TV series. If you are a general practitioner in Harris, in the Outer Hebrides, your nearest specialist in a particular discipline might be in Aberdeen, on the other side of Scotland, but your life and work will have other personal and professional compensations, starting with a beautiful environment, neighbours you know and a stable population of patients. In 2001, the UK government launched a program of “teaching” primary care trusts (PCTs), eventually conferring this status on one trust in each of the 25 strategic health authority areas in England and Wales and making equivalent arrangements in Scotland. Curiously, the background documents for this initiative stressed not education but recruitment and retention of health professionals to work in primary care. Although this seemed a non sequitur, eventually the penny dropped — metropolitan medicine in the UK is, in effect, rural health in Australia turned upside-down. Many of the difficulties faced by practitioners in the two settings are virtually identical: long working hours, often in solo practice; lack of suitable pre-placement training; limited locum cover for holidays and professional development activities; and major concerns about housing, education for children, jobs for partners, and transport. What is not the same is the systematic effort and investment to make a virtue out of necessity. Going beyond early experiments in protected quotas for students from country areas, many Australian medical schools have created departments of rural health, and there are vibrant undergraduate student societies supporting this interest. There are now dedicated postgraduate training schemes for both GPs and specialists seeking a career in the bush, and the profile of the Australian Journal of Rural Health is growing steadily. While medical schools worry that a mismatch between political enthusiasm and dollars invested has increased competition for limited resources, and outer metropolitan areas struggle to attract doctors, country practitioners in Australia from all health disciplines have a growing sense of pride in themselves and their work and are rediscovering the independence and ingenuity that the nation holds as central to its self-image. The UK badly needs to revitalise metropolitan medicine in the same way, but, apart from some dedicated appointments of GPs made under a new system of contracts, this is not happening. The “teaching” budgets of the teaching PCTs are tiny and time-limited, and the university-affiliated hospitals of the biggest cities have one eye on solving the problems referred by their local district general hospitals and the other on research. Any sense of serving a “patch” is much more about defining the geographical boundaries of legitimate referrals than mutual “imprinting” between institution and community. Providing primary care services to their local, inner-urban populations via accident and emergency departments is an inherited responsibility descended directly from giving alms to the poor — a form of noblesse oblige. The features of urban populations that make metropolitan practice exciting — their youth, mixture and mobility — are seen as a source of complication, not stimulation. Nor are the medical schools showing heightened interest. Outside academic departments of primary care, which have been leaders in research on ethnicity, poverty and health, UK medical schools have mostly been lukewarm in their response to requests from government to improve the breadth of access to medical training to include more mature students, entrants from poorer socioeconomic groups, and members of black and other ethnic minorities. The last, in particular, are far more prominent in the large UK cities. In a manner akin to Australian initiatives to attract and graduate rural and Indigenous students, some medical schools have actively recruited from the nominated target groups to new, in-house “foundation programs” to help bridge any gaps between secondary and tertiary education.1 Other schools have “out-sourced” such activities to less prestigious universities eager to boost their more modest reputations as higher-education institutions. While that might be a win–win solution for both parties — as well as for the students — it does highlight a stark difference in degree of connection with pressing issues in the wider community and health service. Australia might have been short-sighted in cutting numbers entering medical training in the early 1990s, but, in trying to limit the contraction, several medical schools responded by earmarking places for students of rural or Indigenous origin. The lead-time is very long, and we can not yet be sure about the careers these pioneers will follow, but the seeds were sown and the trees are growing. Britain, by contrast, has been agonising about metropolitan medicine since at least the late 1970s,2,3 but has taken a decade longer even to begin preparing the soil. Conceivably, recent by-election victories by the Liberal Democrats in economically poor, immigrant-rich urban constituencies might lead the other two major political parties to realise that “things need not be forever thus” and prompt some real reform.

Konrad Jamrozik DPhil, FAFPHM, MFPH · David P Weller MPH, PhD, FRACGP, FAFPHM · Richard F Heller MD, FRCP, FRACP, FAFPHM

Objective: To determine the prevalence of venous thromboembolism (VTE) after total hip replacement (THR), total knee replacement (TKR) or bilateral TKR in a large sample of patients in a major hospital orthopaedic unit.Design, setting and patients: The Mater Misericordiae Hospital, North Sydney, NSW, a 195-bed private hospital. All patients who had THR, TKR or bilateral TKR at the hospital between 1 April 1995 and 31 December 2001 had physical prophylaxis (graduated compression elastic stockings or intermittent pneumatic compression, or both) and chemical prophylaxis (anticoagulant) against VTE. All underwent ultrasonography of both legs before discharge, with a small, symptomatic group also undergoing a ventilation/perfusion lung scan (V/Q scan) and computed tomographic pulmonary angiography.Main outcome measures: Prevalence of deep-vein thrombosis (DVT) and symptomatic pulmonary embolism (PE) before discharge.Results: Among a total of 5999 patients, the pre-discharge prevalence of DVT after THR, TKR or bilateral TKR was 8.9%, 25.6% and 36.9%, respectively. The prevalence of symptomatic non-fatal in-hospital PE was 1.9%, while the prevalence of fatal in-hospital PE was 0.05%.Conclusions: Despite short-term chemical and physical thromboprophylaxis, the prevalence of DVT after lower-limb joint replacement, measured by pre-discharge ultrasonography, was high. The rate of symptomatic non-fatal in-hospital PE was moderate, but fatal in-hospital PE was rare.

Richard F O’Reilly MB BS, FRACP · Ian A Burgess MB BS, FRANZCR · Bernard Zicat MD, FRCSC, FRACS

Objective: An Australian stroke services study (SCOPES) has developed a framework to compare different forms of acute stroke services, the gold standard being localised stroke units. We aimed to use this framework to assess changes in the quality of stroke care over time as a sequential audit process.Design and setting: A retrospective medical record audit comparing 100 sequential stroke admissions (July 2002 to June 2003) two years after institution of a mobile stroke service (MSS) with 100 historical controls (September 1998 to October 1999) at a 260-bed hospital in Melbourne. The MSS results were also compared with stroke units in SCOPES.Main outcome measures: Adherence to quality indicators and standard measures of outcome (complications, length of stay and discharge disability) after implementing the MSS.Results: Significant improvements were seen in prophylaxis for deep-vein thrombosis, incontinence management, premorbid function documentation, frequent neurological observations and early occupational therapy. The MSS demonstrated fewer severe complications (9% versus 24%; P = 0.004), reduced median length of stay (discharged patients: 12.0 days versus 18.5 days; P = 0.003) and more patients were independent at discharge (32% versus 9%; P < 0.001). Comparison with SCOPES stroke units showed our MSS could improve in incontinence management and appropriate use of antiplatelet therapy.Conclusion: Institution of the MSS was associated with improvements in the quality of stroke care. This study demonstrates application of an audit procedure for quality improvement in hospital stroke management and the potential to improve stroke services in smaller centres.

Anneke van der Walt MB ChB · Amanda K Gilligan MB BS, FRACP · Amy G Brodtmann MB BS, FRACP · Dominique A Cadilhac MPubHlth · Dora C Pearce MIT · Geoffrey A Donnan MD

Objective: To assess changes in and factors associated with recent malaria notifications in Western Australia (WA).Design: Retrospective analysis of the WA Notifiable Infectious Diseases Database and enhanced surveillance questionnaires completed by attending medical practitioners.Patients: Cases of malaria notified between January 1990 and December 2001.Main outcome measures: Annual notifications by demographic variables (including age, sex, occupation and place of residence), region/country of acquisition, chemoprophylaxis used, Plasmodium species and outcome.Results: 482 patients were notified (mean age, 31 years; 80% male); 57% lived in Perth, 31% in country areas and 12% in an immigration detention centre. Comparison between the 6-year periods 1990–1995 and 1996–2001 showed that Plasmodium falciparum cases increased from 29 (14%) to 108 (44%; P < 0.001), while Plasmodium vivax cases decreased from 157 (77%) to 122 (50%; P < 0.001); immigrants in detention, defence force personnel and cases from Africa were increasingly represented (P < 0.05 in each case). Only 31% of patients took regular chemoprophylaxis and, among these, the regimen was appropriate in only a quarter. There was a median period of 3 days between symptom onset and diagnosis. One patient died.Conclusions: There has been an increase in P. falciparum cases in WA since 1990. This reflects the influx of immigrants in detention, deployment of military personnel to East Timor and increasing numbers of cases from Africa. A significant number of Australian travellers who developed malaria had not taken chemoprophylaxis either regularly or at all, and, of those who had, the regimen was inadequate in most.

Donnetta M Charles MB BS · Julie Hart MB BS · Wendy A Davis MPH, PhD · Timothy M E Davis DPhil, FRACP · Eleanor Sullivan MPH · Gary K Dowse FAFPHM, MSc

Objectives: To describe the tolerability of mefloquine in Australian soldiers for malaria prophylaxis, including a comparison with doxycycline.Design: Open-label, prospective study and cross-sectional questionnaire and interview.Setting and participants: Two contingents of Australian soldiers, each deployed to East Timor for peacekeeping duties over a 6-month period (April 2001–October 2001 and October 2001–May 2002).Outcome measures: Withdrawals during the study; adverse events relating to mefloquine prophylaxis; willingness to use mefloquine again on deployment.Results: Of 1157 soldiers starting on mefloquine, 75 (6.5%) withdrew because of adverse responses to the drug. There were three serious adverse events of a neuropsychiatric nature, possibly relating to mefloquine. Fifty-seven per cent of soldiers using mefloquine prophylaxis reported at least one adverse event, compared with 56% using doxycycline. The most commonly reported adverse effects of both drugs were sleep disturbance, headache, tiredness and nausea. Of the 968 soldiers still taking mefloquine at the end of their deployments, 94% indicated they would use mefloquine again. Of 388 soldiers taking doxycycline prophylaxis who were deployed with the first mefloquine study contingent, 89% indicated they would use doxycycline again.Conclusions: Mefloquine was generally well tolerated by Australian soldiers and should continue to be used for those intolerant of doxycycline.

Scott J Kitchener MB BS, DrPH, FAFPHM · Peter E Nasveld MB BS, BMedSci(Hons), FACTM · Robin M Gregory BAppSc, MBus · Michael D Edstein MSc, PhD

Metabolic imaging with fluorine-18-fluorodeoxyglucose positron emission tomography (FDG-PET) is increasing rapidly worldwide because of superior accuracy compared with conventional non-invasive techniques used for evaluating cancer. Limited anatomical information from FDG-PET images alone dictates that complementary use with structural imaging is required to optimise benefit. Recently, combined positron emission tomography/computed tomography (PET/CT) scanners have overtaken standalone PET scanners as the most commonly purchased PET devices. We describe our experience of over 5500 scans performed since the first PET/CT scanner in Australia was commissioned at the Peter MacCallum Cancer Centre (PMCC), Melbourne, in January 2002. Clinical indications for PET/CT scans performed at PMCC largely reflect current Medicare reimbursement policy. Advantages of PET/CT include greater patient comfort and higher throughput, greater diagnostic certainty and accuracy, improved biopsy methods, and better treatment planning. We believe PET/CT will underpin more effective and efficient imaging paradigms for many common tumours, and lead to a decrease in imaging costs.

W F Eddie Lau BPharm, FRANZCR · David S Binns DipAppSci, ANMT · Robert E Ware MB BS, FCP(South Africa) · Shakher Ramdave FRACP · Alexander G Pitman BmedSci, FRANZCR · Rodney J Hicks MD, FRACP

A key responsibility of the healthcare system is to develop a sustainable workforce through education and training. The complexity of postgraduate medical education and training in Australia requires: recognition that there are many stakeholders (junior medical officers, registrars, teaching clinicians, health departments, governments, colleges and society) with overlapping but competing interests and responsibilities; a national dialogue to clarify the necessary resource investments and to assign explicit accountabilities; and improved coordination and governance, while maintaining appropriate flexibility. In other countries, stronger mechanisms of governance for oversight of postgraduate medical education have emerged, and Australia can learn from these.

S Bruce Dowton MD, FRACP, FACMG · Marie-Louise Stokes MB BS, FAFPHM · Evan J Rawstron · Philip R Pogson · Mark A Brown MD, FRACP

There has been a relentless increase in resistance of malaria parasites to conventional antimalarial drugs, including chloroquine, sulfadoxine–pyrimethamine and mefloquine. In response to this situation, short-course artemisinin-based combination therapies (ACTs) have been developed. The World Health Organization has endorsed ACT as first-line treatment where the potentially life-threatening parasite Plasmodium falciparum is the predominant infecting species. ACTs combine the rapid schizontocidal activity of an artemisinin derivative (artesunate, artemether or dihydroartemisinin) with a longer-half-life partner drug. Although the use of chloroquine and sulfadoxine–pyrimethamine as partners in ACT improves their efficacy, this may only have value as a short-term measure in patients with a degree of immunity to malaria. Alternative currently available partner drugs include mefloquine, lumefantrine and piperaquine. Artesunate–mefloquine is highly effective but is expensive and side effects (mainly neurotoxicity) can be problematic. Artemether–lumefantrine, the only ACT available in Australia, appears less effective than artesunate–mefloquine and needs to be administered with food to ensure adequate bioavailability. Dihydroartemisinin–piperaquine is highly effective, well tolerated and relatively inexpensive. The goal of potent, safe, easy-to-administer and inexpensive ACTs may see trioxolanes in place of artemisinin derivatives, as well as novel partner drugs such as pyronaridine or naphthoquine, in the future.

Timothy M E Davis DPhil, FRACP · Harin A Karunajeewa FRACP · Kenneth F Ilett PhD

A 28-year-old woman from Sudan who had lived for 9 years in Victoria, Australia, was diagnosed with falciparum malaria 2 months after splenectomy for massive splenomegaly of unknown cause. Chronic falciparum malaria can occasionally present years after leaving endemic areas in partially immune patients. It should be considered in such patients with presentations possibly related to malaria, including splenomegaly, anaemia, or a long history of intermittent fevers and chills. Infection with Plasmodium falciparum is well known as a cause of acute malaria among travellers from endemic areas, such as Africa and South-East Asia. However, chronic infection persisting for months may occur in endemic areas among those with a degree of partial immunity, and cases have been reported in people who left an endemic area up to 5 years previously.1,2 We report a case of falciparum malaria recurring 9 years after the patient migrated from Sudan to Victoria, Australia. The anopheles mosquito vector does not occur in this region of Australia and, if imported, is unlikely to survive for long. The patient initially presented with fever and massive splenomegaly, and the diagnosis of malaria was made after a splenectomy had been performed. Clinical recordA 28-year-old woman from Africa who had been living in Australia for 9 years presented to the emergency department with a one-week history of fever, rigors, abdominal pain, nausea and vomiting. She had no abnormalities on physical examination, apart from mild dehydration, and was discharged with a presumptive diagnosis of viral gastroenteritis. The next day, she presented to the gastroenterology outpatient clinic. Malaria was considered in the differential diagnosis, and she was admitted for further investigation and treatment. Past history: The patient was born in Eritrea and lived there for 6 years, followed by 12 years in Sudan, before migrating to Australia. She had had multiple episodes of malaria while in Africa, but could not recall exactly the drug therapy she received. In Australia, she experienced multiple episodes of nausea, abdominal pain and fever every 3 to 6 months, almost identical to her previous episodes of malaria. Although thick and thin malaria blood films were performed during each of these episodes in Australia, a diagnosis of malaria could not be confirmed. Ten months before current presentation: The patient’s general practitioner noted hepatosplenomegaly and, given her history of probable schistosomiasis exposure through freshwater irrigation canals in East Africa, tested her for schistosomiasis. Stool samples were positive for eggs of Schistosoma mansonii, and schistosoma serological tests were also positive (indirect haemagglutination titre, 256 [positive, > 32]; enzyme immunoassay IgM ratio, 1.5 [positive, > 1.2]). Computed tomography and ultrasound examination of the abdomen demonstrated massive splenomegaly (17 cm) and hepatomegaly (15 cm), with no radiological evidence of portal hypertension. Laboratory studies demonstrated anaemia and neutropenia consistent with hypersplenism. The platelet count could not be measured because of clumping (Box 1). She was treated with praziquantel, but continued to have episodes of abdominal pain and anorexia. Two months before current presentation: Because of these continuing episodes, as well as haematological evidence of hypersplenism, splenectomy was performed after appropriate vaccinations. Repeat thick and thin films before the splenectomy were again negative for malaria, although an immunochromatography card test (ICT) for malarial antigens was not performed. Initial histological examination of the spleen revealed only congestion and some mononuclear-cell infiltration. Current presentation: The patient had not travelled to a malaria-endemic area since arriving in Australia 9 years previously, nor had she been near an airport in the preceding 6 months. Results of haematological and biochemical tests are shown in Box 1. A rapid ICT for malaria antigen was performed (NOW ICT Malaria P.f/P.v. Test, Binax Inc, Portland, USA) and was positive for falciparum malaria (Box 2). The patient was admitted to hospital, and treatment begun with intravenous quinine (600 mg three times daily), as recommended for this form of malaria. The following day, thick and thin blood films were reported as showing 0.5% malaria parasitaemia. Parasite morphology, along with the prolonged period between the last possible exposure to malaria and illness, was considered consistent with Plasmodium malariae infection. Treatment was changed to oral chloroquine (620 mg initially, followed by 310 mg 6 hours later and on Days 2 and 3). Because of the conflicting results of the blood film and ICT test, polymerase chain reaction (PCR) tests for malarial antigens were performed at the Victorian Infectious Diseases Reference Laboratory and at the Institute of Clinical Pathology and Medical Research, Westmead Hospital, Sydney, NSW. Results of both tests a month later confirmed P. falciparum as the causative parasite. Further expert review of the blood film showed features consistent with P. falciparum (Box 3). Progress and follow-up: The fever, vomiting and abdominal pain resolved rapidly, and the patient was discharged after 3 days in hospital. After the positive PCR result for P. falciparum, she was treated again, as an outpatient, with atovaquone plus proguanil (1000 mg and 400 mg, respectively, daily for 3 days). Two weeks after completion of therapy, thick and thin films were found to be negative for malaria parasites. Serological tests for human immunodeficiency virus, hepatitis B and hepatitis C were all negative. A stored blood sample that had been taken 7 months before the current presentation was tested and found to be positive for malaria antibodies (immunofluorescent antibody titre, 160 [positive, > 20]). Further review of the computed tomography scan performed before splenectomy showed no features of chronic liver disease, and detailed histological review of the spleen again demonstrated congestion and a lymphocytic infiltrate (compatible with hyperreactive malarial splenomegaly), but no malarial parasites or pigment. At 6-month review, the patient reported no further symptoms. Screening of her children and husband for malaria (by thick and thin blood films and ICT) and schistosomiasis (by indirect haemagglutination assay) gave negative results. DiscussionThis case is notable because of the prolonged period (9 years) between the last possible exposure to malaria and the diagnosis of falciparum malaria, which was confirmed by PCR. Although it is well recognised that P. malariae infection can persist for many years,3 to our knowledge the longest previously reported delay between exposure and subsequent diagnosis of falciparum malaria is 5 years. In that case, the patient donated blood 5 years after leaving a malarious area, and was found to have falciparum malaria on testing after the recipient of the blood transfusion developed malaria; details in the report are limited.2 Recently, mathematical modelling was used to estimate the duration of P. falciparum infection after interruption of transmission.4 The authors estimated that the maximum duration of infection was about 4 years. Chronic falciparum malaria may occur in people who have lived in endemic areas and have developed partial immunity to the malaria parasite, resulting in low-grade parasitaemia.5 Antimalarial antibodies have been detected in high titres in such patients.6 Massive splenomegaly, now termed “hyperreactive malarial splenomegaly syndrome”,7 is a manifestation of chronic malaria. The demonstration of malarial parasites after splenectomy in patients not recently exposed to malaria raises the possibility of this syndrome.8 Major diagnostic criteria include: massive splenomegaly (> 10 cm) when no other cause can be found; immunity to malaria (ie, demonstration of antimalarial antibodies); and a clinical and immunological response (fall in antibody levels) to antimalarial therapy,9 or a significant reduction in spleen size and improvement in haematological parameters with antimalarial therapy.10 Our case highlights the fact that malaria may still present a major diagnostic challenge. In hindsight, it was likely that our patient had hyperreactive malarial splenomegaly syndrome. Use of other diagnostic tests, including PCR, before splenectomy might have enabled a trial of antimalarial treatment and possibly averted the need for surgery.9 Although thick and thin blood film examination using Field or Giemsa–Wright stain is the established “gold” standard for malaria diagnosis,11 repeated appropriate blood films in our patient before splenectomy were negative. An experienced laboratory can achieve sensitivity of 50 parasites/μL blood (0.001% red blood cells infected), but a survey of UK laboratories found that most achieved sensitivity of 500 parasites/μL blood when compared with a reference laboratory.12 As this case demonstrates, the new, more sensitive ICT card tests can be valuable in difficult-to-diagnose cases of P. falciparum infection. These tests detect circulating P. falciparum histidine-rich protein 2 (HRP-2) in whole blood and provide an immediate result, with sensitivity of 77%–98% and specificity exceeding 95% for falciparum malaria, correlating with counts of 100–300 parasites/μL blood.13 Other ICT kits that detect different antigens are available and can detect all four Plasmodium species.13 Although the sensitivity of these rapid antigen tests is good, a negative result does not exclude malaria. PCR techniques are even more sensitive, detecting levels as low as 5 parasites/μL blood,14 and are available on special request at reference laboratories around Australia. PCR can detect the specific plasmodial species and is therefore useful when morphological diagnosis is difficult, or when clinical suspicion warrants further attempts at diagnosis despite negative results from blood films and ICT. A recent study in Sudan showed that P. falciparum can survive for months in human hosts during the 9-month dry season, when no transmission occurs.5 Many people had ongoing PCR positivity for falciparum malaria, despite having levels of parasitaemia below the threshold for detection on thick and thin blood films. This phenomenon was demonstrated by our patient, whose blood films were repeatedly negative over years. However, splenectomy may unmask underlying chronic P. falciparum infection sufficiently to allow detection of parasitaemia on blood films.15 Chronic falciparum malaria should be considered in the differential diagnosis in patients from endemic areas presenting with symptoms possibly related to malaria, even years after their last possible exposure. Although thick and thin blood films remain the standard laboratory investigation, the relatively inexpensive and more sensitive malaria ICT card test should be a routine adjunct to blood films to detect P. falciparum. PCR testing may be warranted before excluding chronic malaria as the diagnosis. 1 Results of laboratory investigations Test Reference range 7 months before 2 months before* Current admission Haemoglobin (g/L) 115–165 105 104 97 White cell count (× 109/L)† Total 4.0–11.0 2.7 3.1 8.2 Neutrophils 2.0–7.5 0.91 0.95 1.64 Lymphocytes 1.0–4.0 1.39 1.71 5.58 Monocytes 0.1–0.8 0.38 0.38 0.9 Eosinophils < 0.4 0.02 0.07 0.08 Mean cell volume (fL) 82–95 90 85 84 Mean cell Hb concentration (g/L) 320–360 334 331 321 Albumin (g/L) 36–48 39 40 Bilirubin (μmol/L) < 18 23 26 ALP (U/L) 35–104 45 206 ALT (U/L) < 55 16 153 GGT (U/L) < 45 9 43 Urea (mmol/L) 2.5–7.7 4.3 1.9 Creatinine (mmol/L) 0.03–0.11 0.046 0.047 Thick and thin malaria blood films Negative Negative Positive‡ Hb = haemoglobin. ALP = alkaline phosphatase. ALT = alanine aminotransferase. GGT = γ-glutamyltransferase. * Pre-splenectomy. †Platelet count was not recordable because of clumping. ‡Films showed 0.5% parasitaemia; rapid immunochromatography card test and polymerase chain reaction tests were also positive for Plasmodium falciparum. 2 Rapid immunochromatography card test (ICT) for malaria Positive result for Plasmodium falciparum on immunochromatography card test (ICT) in our patient. The card test is performed on whole blood and gives a result within 10 minutes. 3 Thin blood film from the patient The ring form of Plasmodium falciparum (arrow) is apparent in a normal-sized red blood cell.

Benjamin P Howden FRACP, FRCPA · Gautam Vaddadi MB BS · M Lindsay Grayson MD, FRACP, FAFPHM · Joseph Manitta BAppSci(MLS), AIMS, MASM

Bedwetting (nocturnal enuresis) is common. It occurs in up to 20% of 5 year olds and 10% of 10 year olds, with a spontaneous remission rate of 14% per year. Weekly daytime wetting occurs in 5% of children, most of whom (80%) also wet the bed. Bedwetting can have a considerable impact on children and families, affecting a child’s self-esteem and interpersonal relationships, and his or her performance at school. Primary nocturnal enuresis (never consistently dry at night) should be distinguished from secondary nocturnal enuresis (previously dry for at least 6 months). Important risk factors for primary nocturnal enuresis include family history, nocturnal polyuria, impaired sleep arousal and bladder dysfunction. Secondary nocturnal enuresis is more likely to be caused by factors such as urinary tract infections, diabetes mellitus and emotional stress. The treatment for monosymptomatic nocturnal enuresis (bedwetting with no daytime symptoms) is an alarm device, with desmopressin as second-line therapy. Treatment for non-monosymptomatic nocturnal enuresis (bedwetting with daytime symptoms — urgency and frequency, with or without incontinence) should initially focus on the daytime symptoms.

Patrina H Y Caldwell FRACP, PhD · Elisabeth Hodson MRCP, FRACP · Jonathan C Craig FRACP, PhD · Denise Edgar RGN, BN

Peter R Mansfield,* Agnés I Vitry,† James M Wright‡ * Research Fellow, Department of General Practice, University of Adelaide, 34 Methodist Street, Willunga, SA 5172; † Senior Lecturer, QUMPPRC, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide; ‡ Professor, Department of Pharmacology & Therapeutics and Medicine, University of British Columbia, Vancouver, BC, Canada. peter.mansfieldATadelaide.edu.au To the Editor: Langton et al claim that “the celecoxib studies have not demonstrated an increased risk of thrombosis”.1 However, the European Agency for the Evaluation of Medicinal Products concluded that “there is a trend towards a higher MI [myocardial infarction] risk associated with the use of celecoxib compared with naproxen and diclofenac”, and decided that a warning statement was required for all cycloxygenase 2 (COX-2)-selective drugs.2 It is surprising that celecoxib may be worse than diclofenac, because diclofenac is similarly COX-2-selective as celecoxib.3,4 A retrospective analysis of the full CLASS study data for people not taking aspirin found the rates of serious thromboembolic cardiovascular events were celecoxib 1.4% and diclofenac 1.6%, as against 0.7% for ibuprofen.5 These differences were not individually statistically significant, but CLASS was underpowered for cardiovascular events. However, pooling the results for the two similarly COX-2-selective drugs versus ibuprofen reveals a significant difference (relative risk [RR], 2.1; 95% CI, 1.1–3.9). In the full CLASS data, celecoxib did not have a lower rate of complicated ulcers (RR, 0.83; 95% CI, 0.46–1.5) and there was a trend towards more serious adverse events of all types (RR, 1.17; 95% CI, 0.99–1.39) than in the combined ibuprofen and diclofenac groups.3,6 We conclude that the case against all COX-2-selective drugs has not been proven beyond doubt because they have not been studied adequately. However, on the balance of probabilities, they are all likely to have a similar propensity to rofecoxib to increase thrombotic cardiovascular events to some extent. This prothrombotic effect may be reduced by combining them with aspirin, but then the main gastrointestinal benefit is likely to be lost,3,4 so use of such combinations is not justified. Overall, celecoxib is no more effective, more expensive, no safer (and possibly less safe) than non-selective drugs. Meloxicam has not been shown to be any better. COX-2-selective drugs should not be used unless a subpopulation can be identified for whom these drugs have an advantage over the non-selective drugs. In theory, COX-2-selective drugs may be useful for a tiny group of people who are at greater risk of serious harm from gastrointestinal injury than from vascular events. However, there is no proven way to identify such people and there are no relevant trials to guide us. For example, no trials have been done in patients with a history of peptic ulcer. All COX-2-selective drugs should be removed from the market until they have been properly evaluated.

Peter R Mansfield · Agnés I Vitry · James M Wright

Leslie G Cleland,* Michael J James† * Director, † Chief Medical Scientist, Department of Rheumatology, Royal Adelaide Hospital, North Terrace, Adelaide, SA 5000 lclelandATmail.rah.sa.gov.au To the Editor: Langton et al document the history of rofecoxib approval in 1999 and withdrawal in 2004. 1 They also provide an outline of the possible mechanisms for increased cardiovascular risk, which we detailed in the Journal in August 2001. 2 Their editorial raises the issue of whether the increased cardiovascular risk is a class effect of all selective cyclooxygenase 2 (COX-2) inhibitors and notes that no increased risk has been identified to date with celecoxib use. While this is correct, the editorial omits to state that, although several drugs are categorised as “COX-2 inhibitors”, the selectivity for COX-2 over COX-1 inhibition varies greatly between different drugs (see Box). 3 Selectivity for COX-2 for different “COX-2 inhibitors”3 Drug COX-1 / COX-2 (IC50 ratio) Aspirin <0.5 Ibuprofen 0.5 Meloxicam 18 Diclofenac 29 Celecoxib 30 Rofecoxib 267 It is potentially significant that celecoxib is only modestly COX-2 selective compared with rofecoxib. Because COX-2-selective inhibition can lead to selective inhibition of vascular prostacyclin synthesis with little or no effect on vascular or platelet thromboxane synthesis,1 a highly selective COX-2 inhibitor such as rofecoxib is expected to disrupt the balance between antithrombotic prostacyclin and prothrombotic thromboxane. The relatively modest COX-2 selectivity of celecoxib may be one explanation for the lack of adverse cardiovascular effects demonstrated to date. It would also explain its lack of upper gastrointestinal tract protection relative to diclofenac, as both drugs have similar COX-2 selectivity.4 The newer coxibs, like rofecoxib, are significantly more COX-2-selective than celecoxib and, if this selectivity is the basis for the adverse cardiovascular events, then caution is needed with these newer agents. Although the editorial states that trials have not shown increased risk with the newer coxibs, this is not correct. On 15 October 2004, Pfizer announced that valdecoxib, when used for pain management in coronary artery bypass surgery, caused an increased number of adverse cardiovascular events.5 As the editorial states, the VIGOR study with rofecoxib in treating rheumatoid arthritis revealed a greatly increased incidence of adverse cardiovascular events compared with naproxen, and yet rofecoxib sales continued for another four years at a high level. 1 Perhaps the most important question for prescribers arising from the experience with rofecoxib is not whether clinical trial results are conclusive, but how should prescribers respond to apparent conflicts in the medical literature. In such a situation, resort to ethical and legal obligations for disclosure of information will be the prudent approach, as we have detailed.6 For prescribers considering the loss of rofecoxib, some perspective is provided by the following. The number needed to treat (NNT) to cause an increase in one fatal or non-fatal cardiac event in the VIGOR study was 225 (average trial duration was 9 months). In trials with statins in which coronary heart disease was absent at enrolment, the NNT per year to prevent one fatal or non-fatal coronary event was 217 to 256.7

Leslie G Cleland · Michael J James

Hari Manev,* Radmila M Manev† * Professor, † Assistant Professor of Clinical Psychiatry, Department of Psychiatry, University of Illinois at Chicago, 1601 West Taylor Street, MC912, Chicago, Illinois, 60612, USA hmanevATpsych.uic.edu To the Editor: In their editorial on the rofecoxib controversy, Langton et al point out that large-scale but inconclusive studies failed to recognise an increased risk of heart attack and stroke in patients treated with this cyclooxygenase 2 (COX-2) inhibitor.1 Might something still be learned from these studies? Both COX-2 and 5-lipoxygenase (5-LOX) use the same substrate (arachidonic acid) to produce prostaglandins and leukotrienes, respectively. Overactive 5-LOX increases the risk of heart attack and stroke,2,3 and may be involved in the comorbidity of these disorders with anxiety and depression.4 In contrast, COX-2 appears to be cardioprotective. 5 Genetic diversity is responsible for overactive 5-LOX in some individuals and increases their risk for cardiovascular pathology.2,3 It is likely that patients with these alleles might be more susceptible to cardiovascular pathology in the absence of COX-2 activity — that is, be at increased risk of rofecoxib-provoked myocardial infarction and stroke. If possible, retrospective studies should be attempted to determine the genotype of subjects treated with rofecoxib for 5-LOX2 and 5-LOX-activating protein3 polymorphisms and to relate these findings to rates of myocardial infarction and stroke.

Hari Manev · Radmila M Manev

Richard O Day,* Garry G Graham† * Professor of Clinical Pharmacology, University of New South Wales and St Vincent’s Hospital, Victoria Road, Darlinghurst, NSW 2010; † Emeritus Professor of Pharmacology, University of New South Wales, Sydney, NSW r.dayATunsw.edu.au To the Editor: We consider that it is important to comment on the views expressed by Langton et al on the limited value of paracetamol in the treatment of musculoskeletal pain.1 Langton et al recognise that paracetamol is widely recommended as first-line therapy to reduce chronic pain, but they largely dismiss its usefulness, noting that: . . . when used alone paracetamol appears to be less effective than NSAIDs and there are no studies of the safety of the long-term intake of paracetamol.1 However, paracetamol is widely recommended as the first-line drug treatment in the management of osteoarthritis. This is based on its efficacy and safety as compared with nonsteroidal anti-inflammatory drugs (NSAIDs), including cyclooxygenase 2 (COX-2) inhibitors. This position is supported by published guidelines, including those of the American College of Rheumatology2 and the European League of Associations of Rheumatology (EULAR).3 In these guidelines, NSAIDs are recommended for use in moderate to severe osteoarthritis pain (American College of Rheumatology guidelines) or where the pain is unresponsive to paracetamol (EULAR guidelines). Our own Australian Therapeutic Guideline series and National Prescribing Service publications similarly recommend paracetamol as first-line treatment in osteoarthritis4 (see National Prescribing Service, Fact Sheet 8, October 2004 <www.nps.org.au>). The efficacy of paracetamol in comparison with NSAIDs in patients with osteoarthritis has been demonstrated in patients treated for periods ranging from 3 weeks to 2 years, with total daily doses of paracetamol ranging from 2.6 g to 4.0 g,5 but this has been contentious.6,7 In a 2-year study involving 66 patients with osteoarthritis, Williams et al noted a higher withdrawal rate due to side effects in the naproxen group than in the paracetamol group, and slightly less efficacy in the paracetamol group.5 Pincus and colleagues reported that a third of patients receiving paracetamol continued on this treatment for more than 24 months, and that paracetamol was significantly less likely to be discontinued because of toxicity than NSAIDs.8 Thus, although paracetamol is on average less effective in pain reduction compared with NSAIDs,6 the difference in efficacy is small and a substantial proportion of patients can be treated satisfactorily and safely with paracetamol alone.9 Paracetamol remains the appropriate initial treatment for the management of osteo-arthritis. Other medications, such as NSAIDs or COX-2 inhibitors, can be added if patient response is unsatisfactory and the risk–benefit ratios are acceptable. When considering alternative options to rofecoxib, prescribers should also review the non-drug options, such as weight loss, physiotherapy, orthotics, and, where possible, opt for paracetamol first.10 Prescribers need to continue to be mindful of the potential for adverse effects with NSAIDs, particularly in high-risk patients or patients taking concomitant medications. The serious public health problem of upper gastrointestinal tract bleeding caused by NSAIDs is a major consideration in the management of patients with osteoarthritis and becomes more of an issue in the elderly, many of whom have osteoarthritis.

Richard O Day · Garry G Graham

Paul Langton,* Graeme Hankey,† John Eikelboom‡ * Cardiologist, Hollywood Private Hospital, Nedlands, WA; † Neurologist, Stroke Unit, ‡ Haematologist, Royal Perth Hospital, GPO Box X2213, Perth, WA 6847 john.eikelboomAThealth.wa.gov.au In reply: Mansfield, Vitry and Wright take issue with our statement that the celecoxib studies have not shown an increased risk of thrombosis, but provide no data to support their claims, while Cleland and James highlight differences in COX-2 selectivity as a potential explanation for differences in the cardiovascular safety of coxibs. Recently published clinical data confirm an increased risk of cardiovascular events with rofecoxib but not celecoxib, 1 which is consistent with in-vivo studies suggesting that celecoxib but not rofecoxib improves endothelial function,2,3 as well as a significantly lower incidence of oedema and hypertension with celecoxib compared with rofecoxib.4 Nevertheless, we reiterate that it remains incumbent on drug manufacturers and regulatory authorities to demonstrate cardiovascular safety for all new and existing coxibs, including celecoxib. The published coronary artery bypass graft surgery randomised trial referred to by Cleland and James did not report a significant excess of adverse cardiovascular events with valdecoxib,5 nor did two recently published meta-analyses.6,7 However, unpublished data from a second coronary artery bypass graft surgery trial, as well as meta-analyses presented at the American Heart Association meeting in New Orleans in November 2004, indicate that valdecoxib compared with placebo significantly increases the risk of adverse cardiovascular events.8 This is reflected in the recently revised US prescribing information for valdecoxib. 9 Manev and Manev propose enhanced 5-lipoxygenase activity as a mechanism for increased cardiovascular risk in patients treated with COX-2-selective inhibitors. We agree that this important hypothesis merits further study. Day and Graham emphasise paracetamol as first-line drug treatment in the management of osteoarthritis, referring to recently published American, European and Australian guidelines to support their position. We do not dispute the effectiveness of paracetamol to reduce chronic pain. However, data from the 2004 systematic review quoted in our editorial10 demonstrate that nonsteroidal anti-inflammatory drugs are better than paracetamol for pain relief and are often preferred by patients, despite a higher incidence of adverse effects. Only one of the 10 randomised controlled trials included in this systematic review followed patients beyond 3 months; this study reported the primary efficacy outcome only during the first 6 weeks and was not powered for safety.

Paul Langton · Graeme Hankey · John Eikelboom

Ursula Bayliss,* Christopher Cowell,† James Hong,‡ Veronica Wiley,§ Bridget Wicken¶ * Clinical Nurse Consultant, §Principal Scientist, ¶ Clinical Director, NSW Newborn Screening Programme, † Head, Institute of Endocrinology & Diabetes, The Children's Hospital at Westmead, Westmead, NSW 2145; ‡ Paediatrician, North Gosford Medical Centre, North Gosford, NSW. bridgetwATchw.edu.au To the Editor: We report an acute presentation of congenital hypothyroidism in a child almost 6 years old. The condition was not detected by newborn screening. Screening of all neonates started in New South Wales in July 1977, with thyroid stimulating hormone (TSH) being measured in dried blood spots taken from a heel-prick blood sample (currently at 2–3 days of age). A whole-blood TSH level of 40 mIU/L or above triggers a request for full thyroid function testing, whereas with a level of 20–39 mIU/L a second sample is requested. We have screened over 2.3 million babies and detected 690 babies with congenital hypothyroidism. Ten babies with dyshormonogenesis or ectopic thyroid tissue had normal results and were missed by the screening test. Since screening started, “juvenile hypothyroidism” not associated with thyroid antibodies has all but disappeared. A healthy girl aged 5 years 11 months presented with acute dysphagia and drooling. There were no previous dysphagic symptoms. Initially, epiglottitis was suspected; however, at endoscopy a lingual thyroid was visualised at the base of her tongue, and this was confirmed by a technetium scan. She had normal growth and development, with both height and weight at the 50th centiles, a pulse rate of 90 beats/min, and normal deep tendon reflexes. The whole-blood TSH level at newborn screening on Day 3 was 40 mIU/L (reference range [RR], < 20 mIU/L). Thyroid function testing at another hospital on Day 10 showed a serum TSH level of 16.6 mIU/L and a serum free thyroxine (FT4) level within the normal range (12 pmol/L; RR, 11–30 pmol/L). These results were interpreted as normal, whereas, in fact, the TSH level was above the reference range for 10 days of age (< 10 mIU/L), although within the reference range for 2–7 days. On the patient’s admission for treatment of acute dysphagia, the TSH level was 10.9 mIU/L and the FT4 level was 18 pmol/L. A diagnosis was made of compensated hypothyroidism secondary to the ectopically placed lingual thyroid. Thyroxine treatment was commenced on diagnosis, and regular follow-up arranged. Three months after the start of treatment, the results of thyroid function tests (FT4, 17 pmol/L; TSH, 2.7 mIU/L) were within the normal range. Acute presentation of a lingual thyroid is most unusual.1 This case emphasises that further investigations must be performed when thyroid function test results are equivocal. Unfortunately, the thyroid status was considered normal because the FT4 value was within the normal range. All babies whose TSH results remain elevated while the FT4 levels are normal should have a thyroid scan, as we recommend when reporting results.

Ursula Bayliss · Christopher Cowell · James Hong · Veronica Wiley · Bridget Wicken

An elderly man attending a dermatology outpatient clinic for an unrelated skin complaint proudly insisted on demonstrating his simple do-it-yourself (DIY) solution to a deformity of his great toenails (pincer nail) that he had endured for many years. As he slipped off his socks, a number of medical students observing the consultation turned ashen (see Figures). Pincer nails are a transverse overcurvature of the nail, commonly caused either by degenerative osteoarthritis of the distal interphalangeal joints or by ill-fitting shoes. Less commonly, they may be associated with subungual tumours or ingestion of β-blockers. Treatment options for pincer nail usually include bracing (with steel or plastic devices that exert countertension on the nail), surgery to ablate the lateral horns of the nail matrix, or permanent removal of the nail either chemically or surgically.1 Our patient found that, by inserting a stainless steel screw through the free edge of each of his overgrown and overcurved great toenails and into a small broad nut, he was able to satisfactorily correct his deformity by making a series of tightening adjustments over a period of months. Our patient’s novel approach, which is quite unlike that of usual bracing devices, exerted countertension on the ventral aspect of the free edge of the nail. Korean authors have recently described a similar technique using custom-fitted aluminium splints. These are bound with cyanoacrylate adhesive to the ventral nail plate after separating the affected great toenail longitudinally using CO2 laser vaporisation.2 Our patient’s device might begin to create some discomfort as the nail grows longer, requiring repositioning (proximally) to maintain the effect on moulding nail growth, although these considerations were not discussed in the brief consultation with our patient!

Alex Chamberlain MB BS · Annika Smith · Adrian Mar FACD

Bill Young was born in Adelaide on 9 February 1917. After his secondary education at Carey Baptist Grammar School in Melbourne, he worked for the Commonwealth Bank. In 1936, his aunt, Dr Helen Young, herself a Harley Street specialist, wrote offering to support him to study medicine at St Mary’s Hospital, London. Within 3 days, he had paid £30 for his passage and was en route to London. He graduated in medicine from the University of London in 1943. After service in the Royal Navy during World War II, Bill gained a Diploma of Public Health from the University of Manchester in 1947. He returned to Australia in the same year with his wife, Dr Mary Young, and their family. They settled in Hobart, where he and Mary were in general practice together from 1948 to 1987. In addition to full-time general practice, Bill was Medical Officer of Health for both the City of Hobart and the City of Clarence, and was a member of the Medical Council of Tasmania for 34 years, the last three as President. He played a key role in establishing the Medical Benefits Fund, serving on its Council from 1952 to 1987. Bill was a Liberal member of the Tasmanian House of Assembly from 1959 to 1969, including a period as shadow Health Minister. For many years Bill was in the Royal Australian Naval Reserve, retiring in 1972 with the rank of Surgeon Commander. He served in the Korean War and was District Naval Medical Officer in Hobart from 1951 to 1972. Bill was a very good sportsman and excelled in his youth at swimming, water polo and rugby, winning swimming medals at the World University Games and playing rugby for the UK international invitational team, the Barbarians. In Hobart, he contributed his time and skills to a number of community and sporting organisations. Bill was respected by his patients and colleagues as a skilled, compassionate, practical and down-to-earth doctor. He was very gregarious and a wonderful host and derived great pleasure from his large family. A man of great energy and initiative, with exceptional organisational skills, he made a substantial contribution to his profession and to the community. In 1987, he was made a Member of the Order of the British Empire in recognition of his service to the community and to public health. The last years of Bill’s life were devoted to caring for his wife in her final illness. He died in Hobart on 19 November 2003 after a short illness. He is survived by his seven daughters and their families. Judith A Y Straton

Judith A Y Straton

This can’t happen to me! Tackling type 2 diabetes. Tim Bowden. Sydney: Allen and Unwin, 2004 (xiii + 207 pp). ISBN 0 86431 473 6. We know that type 2 diabetes is very common in Australia, that its prevalence is increasing, and that a very large minority of the Australian population have several risk factors for diabetes. These facts are now becoming a matter of public, not just professional, knowledge and will lead to increased public demand for information on the disease, and how to avoid it. There are many excellent sources of information for the person with diabetes, but the diversity of those developing the condition means that additional well-written and accurate accounts are welcome. A first-hand account by someone with a condition has the capacity to make a profound impression on others beyond that of medical texts. Tim Bowden has made an important contribution of this sort that can be recommended with confidence to those newly diagnosed as well as those at risk. Bowden is a broadcast journalist well known for his affable and direct style of communication. He brings these skills to an account of his own diagnosis of type 2 diabetes at a routine medical assessment at the age of 65, and his experiences in learning how to cope with it. This is combined with interviews recounting the experiences of others and with key Australian experts. He provides straightforward information on the range of symptoms, causation, principles of management, monitoring and surveillance for complications. His focus is on the person with diabetes and how he or she can and should deal with the problem, including psychological reactions to the diagnosis and the behavioural adaptations subsequently required. Perhaps another round of editing would have reduced some occasionally irritating repetitiveness, but this book appears to have successfully targeted a public health need and is a welcome addition to currently available publications. Duncan J ToplissDirector Department of Endocrinology and Diabetes Alfred Hospital, Melbourne, VIC

Duncan J Topliss

Which diet? Contrary to recent reports, very-low-carbohydrate diets may not necessarily be better than standard diets, suggest US researchers. They had randomised 160 overweight or obese adults to follow for a year the dietary component of one of four popular programs: Atkins (low carbohydrate), Ornish (low fat) Weight Watchers (low calorie) or Zone (macronutrient balance). The researchers found that each of the four diets led to a similar, and modest, reduction in body weight — about 5 kg or 5% — but only in the minority of participants who decided to keep to the diet for the full year. Further, in these participants, reductions in some of the cardiac risk factors measured (LDL/HDL cholesterol ratio, and serum C-reactive protein and insulin levels) were similar, irrespective of the type of diet. JAMA 2005; 293: 43-53 Beware the return of the fat There is little evidence of the "real-life" effectiveness of major commercial weight loss programs, say the authors of a systematic review. In their search, they found 10 studies that met their rigorous criteria, including some randomised controlled trials of Weight Watchers and one of a medically supervised very-low-calorie diet program. In the largest Weight Watchers trial, participants lost 5% of their initial body weight in 6 months; by 2 years, the weight had crept back up to reduce this loss to 3%. In the very-low-calorie diet trial, people who completed the program lost about 15% to 20% of their initial weight, but had regained about half of this lost weight within one to two years after treatment. Ann Intern Med 2005; 142: 56-66 Vitamin E loses its lustre While the jury may be out on whether antioxidants, like vitamin E, can prevent chronic diseases, authors of a meta-analysis have warned that high-dose vitamin E supplementation may actually be harmful. They analysed data from more than 135 000 patients in 19 clinical trials, finding a dose-dependent relationship between vitamin E supplementation and all-cause mortality. They recommended that high-dose vitamin E supplementation (>400 IU/day) be avoided. Ann Intern Med 2005; 142: 37-46 Overweight? Not us Parents are poor at recognising overweight in themselves and their children, say UK researchers. The researchers studied 277 healthy children and their parents. The whole group was heavier than UK norms. Among the overweight parents, 45% of the fathers and 40% of the mothers judged that their weight was "about right". And, even when children were obese, 57% of the fathers and 33% of the mothers saw their child’s weight as being "about right". In particular, parents are less likely to identify overweight in their sons than in their daughters. BMJ 2005; 330: 23-24 Polypill push Remember the polypill? In 2003, Wald and Law proposed that a daily cocktail of aspirin, folic acid, a statin and three antihypertensive agents, if given to anyone with heart disease and everyone else 55 years of age or older, could dramatically reduce rates of heart attack and stroke. The original proposal, controversially, suggested a whole-population approach, without further trial or screening. Now, an expert group, despite some dissent, has generally supported the conduct of an initial, controlled trial of the polypill in people at intermediate risk of heart disease and stroke, to be followed by further trials. However, according to an extended web version of this news item, a version of the polypill is likely to appear on the market in India by the end of this year. BMJ 2005; 330: 1065-1068 Sorting out "silicone-osis" An Australian study has been unable to confirm that "silicone-osis" exists. It had been previously postulated that silicone-osis might be a new systemic disease, uniquely and causally linked to silicone exposure. The study compared the health status of 487 women exposed to silicone via augmentation mammoplasty for cosmetic reasons between 1979 and 1983 with that of 687 matched women who had had non-silicone-related plastic surgery. Although the existence of a multisystem disorder —characterised by night sweats, lethargy, breast pain, impaired mentation, reflux, paraesthesiae, hand muscle weakness and myalgia — was suggested in the silicone-exposed cohort, this disorder was also present, albeit at a lower frequency, in the silicone-unexposed cohort. Int Med J 2005; 34: 668-676 Dr Ann Gregory, MJA

Ann Gregory